Diabetes mellitus is one of the major diseases in the Western world, afflicting mostly the elderly population (it is estimated that 7% of men and 9% of women over the age of 65 years have diabetes mellitus). Diabetes mellitus is a complex set of diseases that are characterized by high blood glucose levels (hyperglycemia) and altered carbohydrate, lipid and protein metabolism leading to clinical complications such as vascular disorders, eye disorders such as retinopathy, glaucoma and cataracts, nephropathy, diabetic neuropathy and a variety of micro- and macrovessel diseases.
In addition, several serious acute diabetic complications such as diabetic ketoacidosis and lactic acidosis can occur, often with lethal consequences, especially in the elderly [see e.g., Textbook of Diabetes (2nd Edition) J. Pickup and G. Williams, Eds. (1997) Blackwell Science, Oxford].
Most patients can be clinically classified as having either insulin-dependent diabetes mellitus (IDDM or Type-I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM or Type-II diabetes). In the United States about 90% of diabetic patients have Type-II diabetes and most of the remainder suffer from Type-I diabetes.
There is evidence that Type-I diabetes is an autoimmune disease of the pancreatic β-cells leading to their continuous destruction [Srikanta, S. et al. (1983) Ann. Intern.
Med. 99,320-326]. In Type-II diabetes there is no significant loss of β-cells from pancreatic islets, although the β-cells retain their ability to synthesize and secrete insulin and their ability to respond to a glucose challenge is diminished, especially through the first phase of insulin secretion [Cerasi, E. & Luft, R. (1963) Lancet ii: 1359-1361; Cerasi, E. & Luft, R. (1967) Acta ENDOCR. (KBH) 55, 278-304 ; Cerasi, E. & Luft, R. (1967) Acta Endocr. (Kbh.) 55,330-45; Cerasi, E. & Luft. R. (1967) Diabetes 16,615-627; Genuth, S. (1973) Ann. Intern. Med. 79,812-822; Leahy, J. L. et al. (1987) J CLIN. INVEST. 77,908-915; Cerasi, E. In F. M. Ashcroft & S. J. H. Ashcroft, Eds. Insulin: Molecular Biology to Pathology. Oxford University Press (1992), pp. 347-92; Nesher, R. , et al. (1999) Diabetes 48,731-737 ; Cerasi, E., et al. (2001) Diabetes 50 (Suppl. 1): S1-S3].
The search for novel compounds and drugs that can reduce blood glucose levels in diabetic patients is a major topic in diabetes research. Hyperglycemia is the main cause of diabetic complications, such as cardiovascular disease, nephropathy, neuropathy and retinopathy. Most available drugs act primarily on the insulin-secreting cells (i.e., the β-cells in the pancreas) to increase or potentiate insulin release. In many cases these drugs are ineffective due to various reasons, including deterioration of the β-cells and peripheral insulin resistance. It is therefore clear that drugs that increase glucose transport and utilization in peripheral tissues in a non-insulin-dependent manner may be beneficial to treat hyperglycemic diabetic patients.
A major pathophysiological phenomenon in diabetes is the existence of insulin resistance and decreased peripheral glucose utilization [DeFronzo, R. et al (1982) Diabetologia, 313-319]. Three series of observations in diabetic patients indicate that this insulin resistance may itself be associated with the prevailing hyperglycemia. First, most of the defect is in terms of reduction of the maximal velocity of glucose utilization rather than change in the sensitivity to insulin, thus being different from the common insulin resistance like obesity [Olefsky, J. M. et al (1981) Am. J. Med 70,151-168]. Second, the insulin resistance is partially corrected if tested at the patient's habitual hyperglycemic glucose level rather than during acutely induced euglycemia [Revers, R. et al. (1984) R Clin. Invest. 73,664-672, Nesher, R. , et al. (1984) Eur. J Clin. Invest. 17,266-274]. Third, induction of normoglycemia by various means corrects the decreased glucose utilization within several weeks [Nesher et al (1984) ibid; Andres, W. J. et al. (1984) Diabetes 33,634-642; Garvey, W. T. et al. (1985) Diabetes 34, 224-234; Sasson, S. et al. (1986) J: Biol. Chem. 261,16827-16833 ; Sasson, S. et al. (1987) Diabetes 36,1041-1046; Savage, P. J. et al. (1979) J: Clin. Endocrinol. Metab. 48,999-1007; Wertheimer, E. et al. (1990) J Cell. Physiol. 143,330-336]. This suggests that peripheral tissues make use of the glucose mass effect to compensate for the reduced Vmax of uptake. Thus, this insulin resistance, at least partially, seems to be a phenomenon secondary to hyperglycemia. The inventors have recently shown that adaptive down-regulation of glucose transport occurs during hyperglycemia. [Sasson, S. et al. (1986) J. Biol. Chem. 261, 16827-16833; Sasson, S. et al. (1987) Diabetes 36, 1041-1046; Wertheimer, E. et al. (1990) J. Cell. Physiol. 143, 330-336; Cerasi, E. et al. (1989) In Frontiers of Diabetes Research: Current Trends in Non-Insulin-Dependent Diabetes Mellitus (Alberti, K. and Mazze, R., eds.), pp. 309-320, Elsevier Science Publishers, New York; Cerasi, E and Sasson, S. (1992) Journees de Diabetologie, 23-36; Sasson, S. et al (1990) in Frontiers in Diabetes Research II. Lessons from animal diabetes III (ed. E. Shafrir) pp. 355-359, Smith-Gordon, New York; Sasson, S. et al. (1997) Diabetologia 40, 40:30-398; Wertheimer, E. et al. (1991) Proc. Natl. Acad. Sci. (USA) 88, 2525-2529].
The hexose transport system in mammalian cells is subject to complex regulation. The main glucose consumers of the organism, muscle and fat cells, contain two types of glucose transporters: GLUT 1, which is mainly in charge of transporting glucose into the cell under basal conditions, and GLUT 4 which is markedly responsive to insulin and stands for the stimulation of glucose uptake by insulin. The inventors have previously shown that the uptake and utilization of hexose in cultured rat myocytes and myotubes are dependent on the D-glucose concentration to which the cells are pre-exposed [Garvey et al (1985) op cit.; Sasson et al (1987), Wertheimer et al (1990) op cit; Cerasi, E. et al. (1989) op cit.; Cerasi, E and Sasson, S. (1992) op cit.; Wertheimer, E. et al. (1991) op cit.]. Similar effects of glucose withdrawal and refeeding have been reported in cultured L6 [Walker, P. S. et al. (1990) J. Biol. Chem. 265, 1516-1523] and BC3H1 skeletal muscle cells [el-Kabbi, I. M. et al. Biochem. J. 30, 35-40]. In L8 skeletal muscle cells exposed to increasing glucose concentrations, the maximal velocity of hexose transport (Vmax) was reduced in a concentration-dependent manner, while affinity (Km) was unaffected [Sasson, S. and Cerasi, E. (1986) op cit.].
Cytochalasin B binding and Western blotting of enriched plasma- and microsomal-membrane fractions revealed that high glucose concentrations modulated the subcellular distribution of GLUT-1, reducing their number at the plasma membrane of the cell [Sasson, et al (1997); Greco-Perotto, R. et al. (1992) Biochem. J. 286, 157-163]. In addition, glucose reduced time-dependently the GLUT-1 mRNA level in L8 myocytes [Wertheimer et al (1991) op cit.]. Similar autoregulatory effects of glucose were found in a variety of cells (for review, see [Klip, A. et al. (1994) FASEB J. 8, 43-53]). It has been proposed that the downregulation of glucose transport and utilization via this substrate autoregulatory mechanism may play an important role in glucose homeostasis [Cerasi et al (1989), 2 Mathoo et al. (1999) Diabetes 48:1281-1288; Rossetti, L. et al. (1990) Diabetes Care 13, 610-630; Yki-Jarvinen, H. (1990) Diabetologia 33, 579-585]. The inventors have shown [Sasson et al (1997) op cit.] that the accumulation of hexose-6-phosphate in the cells may be related to this mechanism, serving as intermediary between the extracellular glucose concentration and the cellular mechanism that effectuates GLUT translocation.
The inventors have recently observed that high glucose levels affect similarly the cellular distribution of GLUT-4. C2 and L6 skeletal muscle cells and 3T3-L1 adipocytes express both GLUT-1 and GLUT-4; when exposed to a high glucose concentration (20 mM) the density of both transporters in the plasma membrane of the cells is decreased. These findings were obtained by a cell-surface biotinylation technique followed by purification of the biotinylated proteins and Western blotting with specific antisera. Moreover, similar results were confirmed by laser confocal microscopy of the cells.
U.S. Pat. No. 5,468,734 discloses methods and compositions remedying a disease attendant on hyperglycemia, which comprise administering at least one monosaccharide selected from L-arabinose, L-fucose, 2-deoxy-D-galactose, D-xylose, L-xylose, D-ribose, D-ribulose, D-lyxose and D-xylulose. The Specification discloses that it has been found that some pentoses and hexoses are effective in depressing the rise in blood sugar after carbohydrate loading.
U.S. Pat. No. 6,329,344 discloses substituted pentose and hexose monosaccharide derivatives, which exhibit anti-cell adhesion and anti-inflammatory activities. U.S. Pat. No. 5,432,163 discloses derivatives of pentose monosaccharides, which exhibit anti-proliferative and anti-inflammatory activity, as well as methods of treating inflammatory and/or autoimmune disorders employing these compounds. WO01/51058 discloses cyclic ethers of monosaccharides, e.g. 1,5-anhydro-D-fructose (1,5AnFru) or derivatives of 1,5AnFru, and their use in the modulation of glucose metabolism in mammals, in particular in the increase of glucose tolerance.
Given the high incidence of diabetes and hyperglycemia in society, and the serious and sometimes life-threatening complications associated with abnormally high blood glucose levels, there is an urgent need in the medical art to develop new therapeutic approaches to the treatment and/or prevention or hyperglycemia and the complications arising therefrom and to the control and treatment of diabetes.